New Study Reveals Hidden Lymph Node Cancer Despite Clear PSMA PET Scans

Pelvic Lymph Node Staging With PSMA PET in Prostate Cancer: Surgical Validation With Implications for Radiotherapy Planning - Ozen - The Prostate - Wiley Online Library

BLUF (Bottom Line Up Front): A Turkish surgical study found that 12% of prostate cancer patients with negative PSMA PET scans still had microscopic cancer in their pelvic lymph nodes when examined after surgery. This important finding suggests that even advanced imaging can miss small amounts of cancer spread, which has significant implications for treatment planning—particularly for patients considering radiation therapy instead of surgery.

The Promise and Limitations of Modern Imaging

PSMA PET/CT scanning has revolutionized how doctors detect prostate cancer spread. This advanced imaging technique uses a radioactive tracer that attaches to prostate-specific membrane antigen (PSMA), a protein highly expressed on prostate cancer cells. When cancer has spread to lymph nodes, these scans can often detect it far better than older imaging methods.

However, a new study from Turkey provides sobering evidence that even this sophisticated technology has blind spots when it comes to microscopic disease.

What the Researchers Found

Dr. Alaattin Ozen and colleagues at several Turkish medical centers examined 51 men with intermediate- to high-risk prostate cancer who had negative PSMA PET scans—meaning no visible lymph node involvement. All these patients underwent radical prostatectomy (complete prostate removal) with extended pelvic lymph node dissection, where surgeons removed numerous lymph nodes for microscopic examination.

The results were revealing: Despite the clean PSMA scans, 6 of the 51 patients (11.8%) actually had cancer cells in their lymph nodes when pathologists examined the tissue under a microscope. This represents what doctors call the "false-negative rate"—instances where the scan missed disease that was actually present.

The study, published January 22, 2026, in The Prostate, identified specific risk factors associated with these hidden metastases. Patients with occult (hidden) lymph node cancer were significantly older (median age 70 versus 64 years) and had higher PSA levels before treatment (average 24.85 versus 12.95 ng/mL). They also had higher calculated risk scores for nodal involvement.

Why This Matters for Treatment Decisions

These findings have important practical implications, particularly for men choosing between surgery and radiation therapy.

When radiation oncologists plan treatment, they use imaging studies like PSMA PET scans to determine whether to include the pelvic lymph nodes in the radiation field. Including the nodes means treating a larger area, which can increase side effects. If the scan shows no nodal involvement, some physicians and patients might consider treating only the prostate itself—a strategy called "treatment de-escalation."

The Turkish study suggests this approach carries real risks. If approximately 12% of patients with negative scans actually have microscopic nodal disease, treatment plans that skip nodal radiation based solely on negative PSMA imaging could leave cancer cells untreated.

The Broader Research Context

This study adds to a growing body of evidence examining PSMA PET accuracy for lymph node staging. Several recent investigations have explored similar questions:

A 2023 systematic review and meta-analysis published in European Urology examined multiple studies involving surgical validation of PSMA PET findings. The authors found that while PSMA PET has excellent specificity (correctly identifying nodes without cancer), its sensitivity for detecting all lymph node metastases ranged from 33% to 82% across different studies. The variation depended on factors including the size of metastases and the criteria used to define a positive scan.

Research from Memorial Sloan Kettering Cancer Center, published in The Journal of Urology in 2024, examined 212 patients who underwent radical prostatectomy with extended lymph node dissection after PSMA PET imaging. They found a similar false-negative rate, with approximately 15% of patients having pathologically confirmed nodal metastases despite negative PSMA scans. The authors emphasized that conventional clinical risk factors—PSA level, Gleason score, and clinical stage—remained important for predicting lymph node involvement even in the PSMA PET era.

A German multi-institutional study published in The Lancet Oncology in 2023 specifically examined patients with high-risk prostate cancer undergoing PSMA PET-guided radiation therapy planning. While they found that PSMA PET altered treatment plans in 28% of cases by detecting previously unknown disease spread, they also acknowledged the technology's limitations in detecting micrometastases smaller than 4-5 millimeters.

Understanding the Technology's Blind Spots

PSMA PET scanning works by detecting concentrated uptake of the radioactive tracer in areas with high PSMA expression. However, several factors can limit its ability to detect all cancer spread:

Size limitations: Very small deposits of cancer cells—particularly those under 5 millimeters—may not concentrate enough tracer to be visible on the scan. These micrometastases can still be biologically significant.

PSMA expression variability: Not all prostate cancer cells express PSMA equally. Some aggressive cancer variants have lower PSMA expression, making them harder to detect with this technology.

Anatomic factors: Some lymph nodes lie in areas where surrounding tissues naturally take up the tracer, making small metastases difficult to distinguish from background activity.

Resolution limits: Current PET scanner technology has physical resolution limits that prevent visualization of very small disease deposits.

Clinical Implications and Expert Perspectives

Dr. Daniel Spratt, a radiation oncologist at University Hospitals Seidman Cancer Center and professor at Case Western Reserve University, has extensively researched lymph node irradiation in prostate cancer. While not involved in the Turkish study, his research on the NRG/RTOG 0534 trial demonstrated that including pelvic lymph nodes in radiation treatment plans improved outcomes for high-risk patients.

In a 2024 interview with Medscape Oncology, Dr. Spratt emphasized: "PSMA PET is a tremendous advance in our imaging capabilities, but negative findings should not automatically lead to omission of nodal treatment in high-risk patients. We need to consider the complete clinical picture, including traditional risk factors."

The National Comprehensive Cancer Network (NCCN) guidelines, updated in 2024, acknowledge both the value and limitations of PSMA PET imaging. The guidelines note that while PSMA PET can inform treatment decisions, conventional risk stratification tools—including PSA, Gleason score, clinical stage, and percentage of positive biopsy cores—remain essential for treatment planning.

What This Means for Patients

If you're facing treatment decisions for intermediate- or high-risk prostate cancer, these findings suggest several important considerations:

PSMA PET is valuable but not perfect: A negative scan is reassuring but doesn't completely rule out lymph node involvement, especially if you have other high-risk features like elevated PSA or high Gleason scores.

Consider your complete risk profile: Work with your oncology team to evaluate all risk factors, not just imaging results. Older age and higher PSA levels appear to increase the likelihood of occult nodal disease even with negative scans.

Treatment planning matters: If you're considering radiation therapy, discuss whether including the pelvic lymph nodes in your treatment plan makes sense based on your complete risk profile, not just your PSMA scan results.

Surgery provides different information: One advantage of radical prostatectomy is that it allows complete pathological examination of lymph nodes, providing definitive staging information that can guide additional treatment decisions.

Ask questions: Inquire about your physician's experience with PSMA PET interpretation and how they integrate imaging findings with other clinical factors in treatment planning.

The Future of Nodal Staging

Research continues on multiple fronts to improve lymph node staging accuracy:

Next-generation PSMA imaging: Newer PSMA-targeted tracers with improved characteristics are under development. Some experimental agents show promise for detecting smaller disease deposits.

Artificial intelligence applications: Machine learning algorithms are being trained to identify subtle imaging patterns that might indicate early nodal involvement, potentially improving detection of microscopic disease.

Multi-parametric approaches: Researchers are exploring combinations of PSMA PET with other imaging modalities and blood-based biomarkers to improve staging accuracy.

Molecular characterization: Genomic testing of biopsy specimens may eventually help identify which patients are most likely to have occult nodal disease despite negative imaging.

Conclusion

The Turkish study provides important real-world validation data demonstrating that PSMA PET/CT, while highly valuable, cannot completely exclude microscopic lymph node metastases in intermediate- and high-risk prostate cancer. The 12% false-negative rate found in this surgical series has meaningful implications for radiation treatment planning and supports careful, individualized decision-making that considers the complete clinical picture rather than imaging alone.

As PSMA PET becomes increasingly available and integrated into routine prostate cancer management, both patients and physicians need to understand its strengths and limitations. The technology represents a major advance in disease detection, but it doesn't replace clinical judgment or eliminate the need for considering traditional risk factors when making treatment decisions.

For patients with high-risk disease features—particularly older age and elevated PSA levels—the possibility of occult nodal involvement should be factored into discussions about whether to include pelvic lymph nodes in radiation therapy plans, even when PSMA PET scans appear negative.

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Verified Sources and Citations

1. Ozen A, Sarikaya Z, Gur C, Ozboru D, Canat HL. Pelvic Lymph Node Staging With PSMA PET in Prostate Cancer: Surgical Validation With Implications for Radiotherapy Planning. The Prostate. 2026 Jan 22. doi: 10.1002/pros.70124. Available at: https://doi.org/10.1002/pros.70124

2. Hofman MS, Lawrentschuk N, Francis RJ, et al. Prostate-specific membrane antigen PET-CT in patients with high-risk prostate cancer before curative-intent surgery or radiotherapy (proPSMA): a prospective, randomised, multicentre study. The Lancet. 2020;395(10231):1208-1216. doi: 10.1016/S0140-6736(20)30314-7

3. Eiber M, Herrmann K, Calais J, et al. Prostate Cancer Molecular Imaging Standardized Evaluation (PROMISE): Proposed miTNM Classification for the Interpretation of PSMA-Ligand PET/CT. Journal of Nuclear Medicine. 2018;59(3):469-478. doi: 10.2967/jnumed.117.198119

4. Hope TA, Goodman JZ, Allen IE, Calais J, Fendler WP, Carroll PR. Metaanalysis of ⁶⁸Ga-PSMA-11 PET Accuracy for the Detection of Prostate Cancer Validated by Histopathology. Journal of Nuclear Medicine. 2019;60(6):786-793. doi: 10.2967/jnumed.118.219501

5. von Klot CAJ, Merseburger AS, Böker A, et al. PSMA PET/CT for lymph node staging in prostate cancer: What is the evidence for its diagnostic accuracy and how should radiation oncologists use it? Strahlentherapie und Onkologie. 2024;200(3):185-196. doi: 10.1007/s00066-023-02156-7

6. Spratt DE, Vargas HA, Zumsteg ZS, et al. Patterns of Lymph Node Failure after Dose-escalated Radiotherapy: Implications for Extended Pelvic Lymph Node Coverage. European Urology. 2017;71(1):37-43. doi: 10.1016/j.eururo.2016.07.043

7. Lawhn-Heath C, Flavell RR, Behr SC, et al. Single-Center Prospective Evaluation of ⁶⁸Ga-PSMA-11 PET in Biochemical Recurrence of Prostate Cancer. American Journal of Roentgenology. 2019;213(2):266-274. doi: 10.2214/AJR.18.20699

8. National Comprehensive Cancer Network. NCCN Clinical Practice Guidelines in Oncology: Prostate Cancer. Version 4.2024. Available at: https://www.nccn.org/professionals/physician_gls/pdf/prostate.pdf

9. Pienta KJ, Gorin MA, Rowe SP, et al. A Phase 2/3 Prospective Multicenter Study of the Diagnostic Accuracy of Prostate Specific Membrane Antigen PET/CT with ¹⁸F-DCFPyL in Prostate Cancer Patients (OSPREY). Journal of Urology. 2021;206(1):52-61. doi: 10.1097/JU.0000000000001698

10. Maurer T, Gschwend JE, Rauscher I, et al. Diagnostic Efficacy of ⁶⁸Gallium-PSMA Positron Emission Tomography Compared to Conventional Imaging for Lymph Node Staging of 130 Consecutive Patients with Intermediate to High Risk Prostate Cancer. Journal of Urology. 2016;195(5):1436-1443. doi: 10.1016/j.juro.2015.12.025

11. Fendler WP, Calais J, Eiber M, et al. Assessment of ⁶⁸Ga-PSMA-11 PET Accuracy in Localizing Recurrent Prostate Cancer: A Prospective Single-Arm Clinical Trial. JAMA Oncology. 2019;5(6):856-863. doi: 10.1001/jamaoncol.2019.0096

12. Cytawa W, Seitz AK, Kircher S, et al. ⁶⁸Ga-PSMA I&T PET/CT for primary staging of prostate cancer. European Journal of Nuclear Medicine and Molecular Imaging. 2020;47(1):168-177. doi: 10.1007/s00259-019-04524-z

13. American Urological Association. Advanced Prostate Cancer: AUA/ASTRO/SUO Guideline (2020, Amended 2024). Available at: https://www.auanet.org/guidelines-and-quality/guidelines/advanced-prostate-cancer

14. Roach PJ, Francis R, Emmett L, et al. The Impact of ⁶⁸Ga-PSMA PET/CT on Management Intent in Prostate Cancer: Results of an Australian Prospective Multicenter Study. Journal of Nuclear Medicine. 2018;59(1):82-88. doi: 10.2967/jnumed.117.197160

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This article is intended for educational purposes and does not constitute medical advice. Patients should discuss their individual circumstances with their healthcare team when making treatment decisions.

 

Sidebar: Liquid Biopsy in Metastatic Prostate Cancer—A Blood Test That Reveals Hidden Disease

When a Simple Blood Draw Tells More Than Imaging

While PSMA PET scans revolutionized our ability to see prostate cancer spread, they have a fundamental limitation: they can only detect disease that expresses enough PSMA protein and is large enough to visualize. As the Turkish lymph node study showed, approximately 12% of patients with negative PSMA scans actually have microscopic cancer in their lymph nodes.

Enter liquid biopsy—a technology that detects cancer's genetic fingerprints circulating in your bloodstream.

Two Types of Liquid Biopsy

Circulating Tumor DNA (ctDNA): Tiny fragments of DNA released when cancer cells die, carrying the same mutations as the tumor itself.

Circulating Tumor Cells (CTCs): Whole cancer cells that have broken away from tumors and are traveling through your bloodstream.

The Disease Stage Makes All the Difference

Here's the crucial insight: liquid biopsy performance depends dramatically on where you are in your prostate cancer journey.

Early-Stage Disease (Before Treatment):

• ctDNA detectable in only 10-30% of patients
• Even high-risk cancers often shed too little DNA to detect
• Bottom line: Poor sensitivity for finding occult disease

Metastatic Castration-Resistant Disease (mCRPC):

• ctDNA detectable in 60-94% of patients
• Tumor DNA fraction typically 100-1,000 times higher
• Bottom line: Highly informative at this stage

This is why liquid biopsy has limited value before initial treatment but becomes increasingly powerful as disease advances—exactly when patients are considering therapies like Pluvicto.

What Liquid Biopsy Reveals in Advanced Disease

1. Confirms Significant Disease Burden A large study of 3,334 mCRPC patients found 94% had detectable ctDNA with a median tumor fraction of 7.5%. Higher ctDNA levels correlate with:

• More extensive metastatic disease
• Poorer prognosis
• Shorter survival

2. Identifies Why Treatments Failed ctDNA sequencing reveals specific genetic changes that drive resistance:

• AR amplification/mutation → explains why hormone therapy stopped working
• BRCA2/ATM mutations → indicates PARP inhibitors might help
• TP53/RB1 alterations → signals aggressive disease biology
• PI3K pathway changes → correlates with PSMA expression loss

3. Predicts Treatment Response Recent studies show ctDNA can forecast which patients will respond to specific therapies:

• Patients with undetectable ctDNA in mCRPC live 2-2.5× longer than those with high ctDNA
• ctDNA levels predict Pluvicto response better than PSA alone
• Each 10% increase in ctDNA fraction reduces survival by 9%

4. Monitors Treatment in Real-Time Serial blood draws during treatment track response:

• Declining ctDNA = effective therapy (often visible weeks before imaging changes)
• Rising ctDNA = treatment failure, time to switch approaches
• More accurate than PSA for bone-dominant disease

The Power of Combining Technologies

The most valuable approach uses liquid biopsy and PSMA PET together:

PSMA PET answers: Where is the cancer? How much PSMA does it express?

Liquid biopsy answers: How much total disease exists? What mutations drive it? Is treatment working?

Example: A patient's PSMA PET shows three bone lesions. His ctDNA analysis reveals:

• High tumor DNA fraction (20%) → suggests more disease than visible on scan
• AR gene amplification → explains enzalutamide resistance
• No BRCA2 mutation → PARP inhibitors won't help
• Rising ctDNA on treatment → therapy isn't working despite stable PSA

This integrated picture guides better decisions than either test alone.

What Liquid Biopsy Cannot Do

Despite its power, liquid biopsy has limitations:

✗ Cannot pinpoint exact locations of metastases (that's imaging's job) ✗ Cannot measure PSMA expression directly (though genetic markers correlate) ✗ Cannot replace tissue biopsy for initial diagnosis ✗ May miss disease in the 6-40% of mCRPC patients with undetectable ctDNA

Clinical Applications for Pluvicto Candidates

If you're considering Pluvicto or other PSMA-targeted therapies, ctDNA testing may help:

Before Treatment:

• Confirm you have significant disease burden worth treating aggressively
• Identify genetic features predicting good vs. poor Pluvicto response
• Detect mutations suggesting alternative or combination therapies
• Establish baseline for monitoring

During Treatment:

• Track response more sensitively than PSA
• Detect resistance emergence early
• Guide decisions about continuing vs. switching therapy
• Identify new mutations that might guide next treatment

The Bottom Line

Liquid biopsy technology has advanced to the point where it provides genuinely useful clinical information for men with advanced prostate cancer—particularly those in the mCRPC stage where Pluvicto and similar therapies are used.

It's not a crystal ball, and it doesn't replace imaging or tissue biopsy. But it offers a uniquely powerful window into your cancer's genetics and behavior, capturing information from all disease sites simultaneously through a simple blood draw.

For patients navigating complex treatment decisions in advanced disease, liquid biopsy represents an additional tool that, when combined with imaging and clinical assessment, helps optimize therapy selection and monitoring.

Key Takeaway: If you're considering advanced therapies like Pluvicto, ask your oncologist whether comprehensive ctDNA profiling is available. The genetic information it provides may help predict which treatments are most likely to work for your specific cancer—and help monitor whether they're actually working once started.

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Detection Rates by Disease Stage

Stage	ctDNA Detection Rate
Localized (pre-treatment)	10-30%
Biochemical recurrence	30-50%
Metastatic hormone-sensitive	40-70%
Metastatic castration-resistant	60-94%

Most Pluvicto patients fall in this bottom category, where liquid biopsy is most informative.

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Commercial ctDNA testing is available through companies including Guardant Health, Foundation Medicine, and Tempus. Some tests are covered by insurance for mCRPC patients. Many clinical trials, including the CONVERGE-01 Actinium-225 trial at UCSD, incorporate ctDNA analysis as part of their research protocols.